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Activation-induced cytidine deaminase action is strongly stimulated by mutations of the THO complex.

ABSTRACT: Activation-induced cytidine deaminase (AID) is a B cell enzyme essential for Ig somatic hypermutation and class switch recombination. AID acts on ssDNA, and switch regions of Ig genes, a target of AID, form R-loops that contain ssDNA. Nevertheless, how AID action is specifically targeted to particular DNA sequences is not clear. Because mutations altering cotranscriptional messenger ribonucleoprotein (mRNP) formation such as those in THO/TREX in yeast promote R-loops, we investigated whether the cotranscriptional assembly of mRNPs could affect AID targeting. Here we show that AID action is transcription-dependent in yeast and that strong and transcription-dependent hypermutation and hyperrecombination are induced by AID if cells are deprived of THO. In these strains AID-induced mutations occurred preferentially at WRC motifs in the nontranscribed DNA strand. We propose that a suboptimal cotranscriptional mRNP assembly at particular DNA regions could play an important role in Ig diversification and genome dynamics.

SUBMITTER: Gomez-Gonzalez B

PROVIDER: S-EPMC1895963 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Activation-induced cytidine deaminase action is strongly stimulated by mutations of the THO complex.

Gómez-González Belén B Aguilera Andrés A

Proceedings of the National Academy of Sciences of the United States of America 20070508 20

Activation-induced cytidine deaminase (AID) is a B cell enzyme essential for Ig somatic hypermutation and class switch recombination. AID acts on ssDNA, and switch regions of Ig genes, a target of AID, form R-loops that contain ssDNA. Nevertheless, how AID action is specifically targeted to particular DNA sequences is not clear. Because mutations altering cotranscriptional messenger ribonucleoprotein (mRNP) formation such as those in THO/TREX in yeast promote R-loops, we investigated whether the ...[more]

PMID: 17488823

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Project description:Complex human-pathogenic retroviruses cause high morbidity and mortality worldwide, but resist antiviral drugs and vaccine development due to evasion of the immune response. A complex retrovirus, mouse mammary tumor virus (MMTV), requires replication in B and T lymphocytes for mammary gland transmission and is antagonized by the innate immune restriction factor murine Apobec3 (mA3). To determine whether the regulatory/accessory protein Rem affects innate responses to MMTV, a splice-donor mutant (MMTV-SD) lacking Rem expression was injected into BALB/c mice. Mammary tumors induced by MMTV-SD had a lower proviral load, lower incidence, and longer latency than mammary tumors induced by wild-type MMTV (MMTV-WT). MMTV-SD proviruses had many G-to-A mutations on the proviral plus strand, but also C-to-T transitions within WRC motifs. Similarly, a lymphomagenic MMTV variant lacking Rem expression showed decreased proviral loads and increased WRC motif mutations relative to those in wild-type-virus-induced tumors, consistent with activation-induced cytidine deaminase (AID) mutagenesis in lymphoid cells. These mutations are typical of the Apobec family member AID, a B-cell-specific mutagenic protein involved in antibody variable region hypermutation. In contrast, mutations in WRC motifs and proviral loads were similar in MMTV-WT and MMTV-SD proviruses from tumors in AID-insufficient mice. AID was not packaged in MMTV virions. Rem coexpression in transfection experiments led to AID proteasomal degradation. Our data suggest that rem specifies a human-pathogenic immunodeficiency virus type 1 (HIV-1) Vif-like protein that inhibits AID and antagonizes innate immunity during MMTV replication in lymphocytes.IMPORTANCE Complex retroviruses, such as human-pathogenic immunodeficiency virus type 1 (HIV-1), cause many human deaths. These retroviruses produce lifelong infections through viral proteins that interfere with host immunity. The complex retrovirus mouse mammary tumor virus (MMTV) allows for studies of host-pathogen interactions not possible in humans. A mutation preventing expression of the MMTV Rem protein in two different MMTV strains decreased proviral loads in tumors and increased viral genome mutations typical of an evolutionarily ancient enzyme, AID. Although the presence of AID generally improves antibody-based immunity, it may contribute to human cancer progression. We observed that coexpression of MMTV Rem and AID led to AID destruction. Our results suggest that Rem is the first known protein inhibitor of AID and that further experiments could lead to new disease treatments.

Dataset Information

Activation-induced cytidine deaminase action is strongly stimulated by mutations of the THO complex.

Publications

Activation-induced cytidine deaminase action is strongly stimulated by mutations of the THO complex.

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